The gamma 134.5 protein, present both in herpes simplex virus 1 and 2 (HSV), plays an essential role in viral virulence. Unlike wild-type virus, HSV mutants that lack the gamma 134.5 gene are incapable of replicating and causing diseases. However, the underlying mechanisms are not incompletely understood. The major goal of the proposed research is to investigate the biological functions of gamma 134.5 during HSV infection. HSV gamma 134.5 contains an amino-terminal domain, a linker region of triplet repeats, and a carboxyl- terminal domain. A critical function of gamma 134.5 is to block the interferon response mediated by double-stranded RNA dependent protein kinase PKR. In addition, gamma 134.5 is involved in virus egress. This activity maps to the amino-terminus of gamma 134.5 that shuttles between the nucleus, nucleolus and cytoplasm. It is thought that coordinated actions of functional elements in the gamma 134.5 protein and cellular factors facilitate virus egress that contributes to viral virulence. To test this hypothesis, mutational analysis will be performed to define functional modules of gamma 134.5. Recombinant viruses will be constructed to study viral replication, spread, and the interferon response in infected cells. Experiments will also be performed to identify targets of gamma 134.5. Furthermore, studies will be carried out to explore the molecular nature by which gamma 134.5 promotes viral infection. Taken together, these studies will provide insights into the mechanisms of HSV pathogenesis. PUBLIC HEALTH RELEVANCE: In summary, herpes simplex viruses are human pathogens that cause diseases such as genital herpes, keratitis, and encephalitis. This research is designed to investigate how a pathogenic factor of herpes simplex viruses facilitates viral infection, which may lead to the development of novel vaccines and antiviral therapeutics.